{"id":377,"date":"2025-10-10T22:38:12","date_gmt":"2025-10-10T22:38:12","guid":{"rendered":"https:\/\/mrivas.su.domains\/gbe\/?p=377"},"modified":"2025-10-10T22:38:12","modified_gmt":"2025-10-10T22:38:12","slug":"why-rare-variants-and-not-common-variants-are-best-for-therapeutic-hypotheses","status":"publish","type":"post","link":"https:\/\/mrivas.su.domains\/gbe\/uncategorized\/why-rare-variants-and-not-common-variants-are-best-for-therapeutic-hypotheses\/","title":{"rendered":"Why rare variants, and not common variants, are best for therapeutic hypotheses"},"content":{"rendered":"\n<p>Although cumulatively common variants appear to explain a large fraction of the heritability of most human traits, they offer little benefit to drug developers. For one, it is quite difficult to pinpoint the culprit genes, much less the culprit variants, and for two the functional consequences are poorly understood. <\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img decoding=\"async\" src=\"https:\/\/biobankengine.stanford.edu\/static\/PRSmap\/PRSmap_v2\/per_trait\/INI50.plot.png\" alt=\"\"\/><figcaption class=\"wp-element-caption\">Relationship between polygenic risk score (x-axis) and standing height (y-axis) in UK Biobank. <\/figcaption><\/figure>\n\n\n\n<p>Unlike common variants, rare variants offer an alternative view that makes it easier to distinguish causal relationships due to breaking of the correlation structure between variants and the complex trait association support by multiple independent variants.<\/p>\n\n\n\n<p>We&#8217;ve written some papers on looking at multiple properties of rare variants to jointly dissect their contribution: <br>1. by looking at the effect of the genetic variants by protein structure impact prediction;<br>2. by looking at whether the genetic variants lead to loss of gene function; and<br>3. by looking at whether information about what is happening to their neighbors is informative about what is happening to you and your relationship to the human trait of interest. <br><\/p>\n\n\n\n<p>Below is an example where we see that the probability of pathogenicity, i.e. a probability determined by the predicted impact of the mutation on protein folding by a deep learning algorithm, is related to the observed values of red blood cell count in individuals that carry those mutations. The location of mutations that are pathogenic are shown in Figure panel (b).<\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"731\" height=\"1399\" src=\"https:\/\/mrivas.su.domains\/gbe\/wp-content\/uploads\/2025\/10\/nihpp-2025.01.23.634522v1-f0004.jpg\" alt=\"\" class=\"wp-image-379\" srcset=\"https:\/\/mrivas.su.domains\/gbe\/wp-content\/uploads\/2025\/10\/nihpp-2025.01.23.634522v1-f0004.jpg 731w, https:\/\/mrivas.su.domains\/gbe\/wp-content\/uploads\/2025\/10\/nihpp-2025.01.23.634522v1-f0004-157x300.jpg 157w, https:\/\/mrivas.su.domains\/gbe\/wp-content\/uploads\/2025\/10\/nihpp-2025.01.23.634522v1-f0004-535x1024.jpg 535w\" sizes=\"auto, (max-width: 731px) 100vw, 731px\" \/><\/figure>\n","protected":false},"excerpt":{"rendered":"<p>Although cumulatively common variants appear to explain a large fraction of the heritability of most human traits, they offer little benefit to drug developers. For one, it is quite difficult to pinpoint the culprit genes, much less the culprit variants, and for two the functional consequences are poorly understood. Unlike common variants, rare variants offer [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-377","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"_links":{"self":[{"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/posts\/377","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/comments?post=377"}],"version-history":[{"count":2,"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/posts\/377\/revisions"}],"predecessor-version":[{"id":380,"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/posts\/377\/revisions\/380"}],"wp:attachment":[{"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/media?parent=377"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/categories?post=377"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/mrivas.su.domains\/gbe\/wp-json\/wp\/v2\/tags?post=377"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}